Effects of Chronic Estrogen on TIDA Neurons: Role of Cytokines and NO

围绝经期是女性生命中最复杂和最不了解的状态之一。许多 与这种状态相关的健康风险被认为是由于雌激素水平的降低， 雌激素可以预防围绝经期妇女面临的健康风险。然而，雌激素波动 在围绝经期，如果在月经前期和卵泡期增加。最近的临床 试验表明绝经后妇女长期服用雌激素化合物可能 增加患多种疾病的风险。因此，研究雌激素的作用具有重要意义 暴露于各种器官系统。迄今为止的研究表明，雌激素对大脑的影响是 有利于然而，这些报道的影响涉及大脑的非下丘脑区域。的影响 调节几种关键身体功能的下丘脑的慢性雌激素暴露还没有被发现。 研究了这是至关重要的，因为妇女长期使用雌激素制剂， 在成年期暴露于内源性雌激素中。本建议侧重于以下方面的影响 慢性雌激素暴露于下丘脑的雌激素敏感神经元系统之一，即， 结节漏斗多巴胺能（TIDA）系统。从TIDA神经元释放的多巴胺（DA）抑制 垂体前叶分泌催乳素（PRL）。TIDA活动中与放射性相关的减少与以下因素有关： 高催乳素血症和动物模型中乳腺和垂体肿瘤的出现。的机制 TIDA神经元功能丧失的原因尚不清楚。在本申请中，我们提出了一种新颖的 假设和一个有趣模型来研究雌激素如何影响TIDA神经元并增加PRL 程度. 这一系列的研究很重要，因为女性不仅在HRT中长期使用雌激素， 也暴露在环境雌激素中。长期暴露于雌激素和PRL水平升高 可能会增加患乳腺癌的风险。

Perimenopause is one of the most complex and least understood states of a woman's life. Many of the health risks associated with this state were believed to be due to decreases in estrogen levels and that estrogen could protect against health risks faced by perimenopausal women. However, estrogen fluctuates during perimenopause and if at all increases during the premenstrual and follicular phases. Recent clinical trials have shown that chronic administration of estrogenic compounds in postmenopausal women may increase the risk for several diseases. Therefore, it is important to investigate the effects of estrogen exposure on various organ systems. Studies so far indicate that estrogen's effects in the brain are beneficial. These reported effects, however, deal with non-hypothalamic regions of the brain. The effects of chronic estrogen exposure on the hypothalamus which regulates several key body functions have not been investigated. This is critical because women use estrogenic preparations on a prolonged basis and are exposed to endogenous estrogen throughout their adulthood. This proposal focuses on the effects of chronic estrogen exposure on one of the estrogen sensitive neuronal systems of the hypothalamus, namely, the tuberoinfundibular dopaminergic (TIDA) system. Dopamine (DA) released from TIDA neurons inhibits prolactin (PRL) secretion from the anterior pituitary. Age-related reductions in TIDA activity is associated with hyperprolactinemia and appearance of mammary and pitutiary tumors in animal models. The mechanisms behind the loss of TIDA neuronal function is not clear. In this application, we are proposing a novel hypothesis and an interesting model to study how estrogen could affect TIDA neurons and increase PRL levels. This series of studies is important because women not only use estrogen on a long-term basis in HRT but are also exposed to environmental estrogens. Prolonged exposure to estrogen and elevated levels of PRL may promote the risk for breast cancer.